The present invention relates to antibacterial agents of the carbapenem class, in which the 2-position sidechain is characterized by an azafluoren-9-one moiety, substituted by various anionic and neutral substituents, as described in more detail further below.
Thienamycin was an early carbapenem antibacterial agent having a broad spectrum; it has the following formula: ##STR2## Later, N-formimidoyl thienamycin was discovered; it has the formula: ##STR3##
The 2-(aza-9-fluorenonyl)-carbapenems of the present invention are not characterized by a broad antibacterial spectrum such as that of thienamycin or N-formimidoyl thienamycin. Rather, their spectrum of activity is largely limited to gram positive microorganisms, especially methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS). The antibacterial compounds of the present invention thus comprise an important contribution to therapy of these difficult to control pathogens. Morever, there is an increasing need for agents effective against such pathogens (MRSA/MRCNS) which are at the same time safe, i.e., free from undesirable toxic side effects. No .beta.-lactam antibacterial has yet been found which meets these requirements. And, the current agent of choice, vancomycin, a glycopeptide antibacterial, is experiencing an ever increasing amount of resistance in the MRSA/MRCNS pathogens.
More recently, carbapenem antibacterial agents have been described which have a 2-substituent which is an aryl moiety optionally substituted by, e.g., aminomethyl and substituted aminomethyl. These agents are described in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have the formula: ##STR4##
EP-A-0277 743 describes a particular class of compounds of the formula: ##STR5## but this limited teaching in no way suggests the totally different compounds of the present invention, nor their surprisingly better anti-MRSA/MRCNS activity.
Recently patents have issued disclosing the 2-substituted carbapenems having anti-MRSA/MRCNS activity (see U.S. Pat. Nos. 5,004,739; 5,004,740; 5,011,832; 5,025,008; 5,032,587; 5,132,422, all assigned to Merck & Co., Inc.). Particularly, patents have issued disclosing 2-and 3-fluoren-9-onyl-2-carbapenems having anti-MRSA/MRCNS activity (see U.S. Pat. Nos. 5,025,007 and 5,034,384). However, there is no published description of or suggestion of a substituted azafluoren-9-onyl 2-substituent such as characterizes the compounds of the present invention.